Obesity is known to be associated with an overactive endocannabinoid (EC) system. However, the mechanisms responsible for increased ECs in obesity are poorly understood. D’Eon et al. therefore examined the role of obesity and insulin resistance in the regulation and/or dysregulation of intracellular ECs in 3T3-L1 adipocytes and diet-induced obese (DIO) mice. The authors provided evidence that adipocyte insulin resistance contributes to a dysfunctional EC system in obesity. They also suggested that adipocytes have a dual role in EC metabolism through both local regulation of intracellular adipose tissue ECs and regulation of circulating ECs through membrane bound EC-degrading enzyme fatty acid amide hydrolase (FAAH). Both of these systems were dysregulated by insulin resistance, contributing to the obesity-associated overactivation of the EC system. In normalized adipocytes, the authors found that insulin treatment reduced intracellular ECs [2-arachidonylglycerol (2-AG) and anandamide (AEA)] likely by increasing expression of EC metabolism enzymes [monoacyl glycerol lipase (MAGL) and FAAH]. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression were disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. These findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and reduce intracellular EC levels in response to insulin stimulation. This study established that adipocyte insulin resistance contributes to EC system dysregulation in obesity and thereby provides a novel investigative avenue in the therapy of metabolic disorders.
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